ALPHA-(2-LOWER ALKYL-2-{8 2-(6-LKOXY OR TERTIARY AMINO-1,2,3,4-TETRAHYDRONAPHTH-1-YLIDEN) ethyl{9 -3-OXO CYCLO-PERET-1-YLIDENAMINOXY OR OXO HYDROZINO) ALKONIC ACID AND ASYMMETRIC FORCES FOR THEIR PRODUCTION

ABSTRACT

Process for the selective manufacture of novel steroid intermediates possessing either the d or l stereo-chemical configuration.

tates Patent Inventors Appl. No. Filed Patented Assignee ALPHA-{Z-LOWERALKYL-2-[2-(6-ALKOXY OR TERTIARY AMlNOl,2,3,4-TETRAHYDRO-NAPHTH-l-YLIDEN)ETHYL]-3-OXOCYCLOPENT- l-YLIDENAMINOXY OR HYDRAZINO}ALKANOIC ACIDS AND ASYMMETRKC PROCESS FOR THEIR PRODUCTION 11 Claims, N0Drawings us. on ..I.f. 2 0/2472 R, 260/239 BF, 260/268 BC, 260/294 0,260/326.3, 260/518 R, 260/519, 260/999 [51] Jim. Cll C0711 87/42 [50]Field 01? Search 260/568, 519, 247.12, 326.3. 268, 294, 239

References Cited 0TH ER REFERENCES Fieser & Fieser Organic Chemistry 3rdEd. Reinhold Pub. Co. p. 265 I956) Primary ExaminerAlex Mazel AssistantExaminer-Jose Tovar Attorneys-John M. Brown, John J. Kolano, Elliot N.

Schubert, Walter C. Ramm and l-lelmuth A. Wegner ABSTRACT: Process forthe selective manufacture of novel steroid intermediates possessingeither the d or 1 stereo-chemical configuration.

ALPHA-(Z-LOWER ALKYL-2-[2-(6-LKOXY R TERTIARY AMINO-l,2,3,4-TETRAIIYDRONA1PIITH- 1 YLIDEN) ETIIYL1-3-0X0 CYCLO-PERET-lYLIDIENAMINOXY OR 0X0 HYDROZINO) ALKONIC ACID AND ASYMMETRIC FORCES FORTHEIR PRODUCTION The present invention is concerned with a process forthe selective manufacture of novel intermediates possessing either the dor I stereochemical configuration and, in particular, intermediates ofthe following structural formula wherein R is a lower alkyl radical, Ris a 2-[2-(6-substitutedl ,2,3,4-tetrahydronaphth- 1 -yliden )ethyl]radical, in which the 6-substituent is lower alkoxy, (optionallyalkyiated) amino or heterocycloaliphatic amino or a radical of theformula W being a methyl or -(CI-I COO(lower alkyl) radical and acarbonyl or ketalized carbonyl function, and A, B and D are unidenticalmembers selected from the group consisting of hydrogen and (optionallysubstituted) hydrocarbon radicals such that there is an appreciabledifference in size between the two groups.

The lower alkyl radicals denoted in that structural representation aretypified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and thebranched-chain isomers thereof.

Examples of the lower alkoxy radicals represented therein are methoxy,ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy and thecorresponding branched-chain isomers.

The heterocycloaliphatic amino radicals represented are, for example,pyrrolidino, piperidino, morpholino, pipecolino, piperazino andhexamethylenimino.

Illustrative of the (optionally substituted) hydrocarbon radicalsencompassed by A, B and D are aryl radicals such as phenyl, xylyl,tolyl, naphthyl, also aralkyl radicals such as benzyl, phenethyl, etc.,and lower alkyl radicals as hereinbefore exemplified.

The novel process of the present invention is useful in the variousrecently developed, commercially important steroid total synthesismethods known to the art. Those various methods suffer from the samedisadvantage, i.e. an inability to produce the desired steroids havingthe stereochemical configuration of naturally occurring substancesunaccompanied by the formation of an equal amount of the correspondingenantiomorphic form. The most satisfactory solution to that problemwould involve the asymmetric synthesis of an intermediate formed earlyin the total synthesis scheme. Attempts at achieving such a result havebeen described recently by Gibian et al., Tetrahedron Letters, 2 l 2321(i966), Bucourt et al., Bull. Soc. Chim., I967, 561 and Bellet et al.,Campt. Rend. Acad. Sci., 263, 88 (I966). Gibian et al. thus describedthe stereoselective reduction of one of the carbonyl groups of 2-methyl-2-[2-(6-methoxyl ,2,3,4-tetrahydronaphthlyliden)ethyllcyclopentane-l ,3-dione by the action of a microorganism ofthe Saccharomyces genus. That process, however, suffers from a number ofdisadvantages peculiar to LII microbiological methods, e. g. prolongedreaction time, utilization of very dilute solutions thus necessitatinglarge reaction volumes, time-consuming and cumbersome procedures. Inaddition, those methods result in l7-hydroxy intermediates, which mustbe reoxidized to yield the necessary l7-keto group. Bucourt et al.describe the reaction of the aforementioned diketone, i.e. 2-methyl-2-l2.-(6-methoxy-l,2,3,4- tetrahydronaphthl -yliden)ethyllcyclopentanel,3-dione with L-tartramic acid hydrazide to afford the correspondinghydrazone. By virtue of its lesser solubility, one of the two possiblediastereoisomers is obtained in predominant amount. Fortuitously, thatpredominant isomer possesses the stereochemical configuration at thenewly-produced asymmetric center which is characteristic of naturallyoccurring steroids.

The process of the present invention involves an asymmetric synthesis,but, in contrast to that of Bucourt et al., does not depend uponrelative solubilities of the possible diastereoisomers. To the contrary,the success of the present process results from the surprising andunexpected discovery that one of the two carbonyl groups of the steroidintermediate represented by the following structural formula wherein Rand R are as hereinbefore defined, will selectively react with anoptically active carbonyl reagent of the following structural formulawherein A, B and D are as hereinbefore defined, to form unequal amountsof the diastereomeric intermediates.

The diketo steroid intermediates utilized as starting materials in thepresent process are derived from 2-alkylcyclopentane-l,3-diones and aremanufactured by methods described by Pappo, U.S. Pat. No. 3,337,542,issued Aug. 22, 1967; H. Smith et al., Experientia, XIX, 394 (l963);Boyce and Whitehurst, J. Chem. 800.,1959, 2022; Velluz et aL, Compt.Rend. Acad. Sci., 257, 3086 (1963) and: Bellet et al., Compr. Rend.Acad. Sci., 263, 88 (1966).

The aforementioned optically active carbonyl reagents are exemplified byamines, such as a-phenethylamine, and aaminoxycarboxylic acid anda-hydrazinocarboxylic acid derivatives such as those represented by thefollowing formula wherein R is a hydrocarbon radical, Z is an oxa orimino group and Y is an hydroxy, alkoxy or (optionally substituted)amino radical. Similarly useful are the corresponding amine salts, e.g.the hydrochloride.

Especially preferred optically active carbonyl reagents are thosewherein Y is an hydroxy group, i.e. the carboxylic acids, and Z is anoxa or an imino group. These reagents correspond to the knowna-aminocarboxylic acids of both natural and unnatural configuration, asexemplified by alanine, leucine, phenylalanine, methionine, arginine andserine.

Examples of suitable a-aminoxycarboxylic acid carbonyl reagents aredisclosed by Testa et al., Helv. Chim. Acta., 46, 766 (1963) and inFrench patent 1316 M, published May 14, 1962,

while suitable a-hydrazinocarboxylic acids are described by Niedrich etal.,Jour. Prakt. Chem., 27, 108 (1965).

A preferred embodiment of the present invention consists of the processfor the manufacture of the novel intermediates represented by thefollowing structural formula wherein R, R, X and Z are as hereinbeforedefined. The aforementioned a- 2-methyl-2[ 2-( o-morpholino-l ,2 ,3,4-tetrahydronaphthl -yliden )ethyl l-3-oxocyclopentl-ylidenaminoxylpropionic acid, for example, is heated in benzene withp-toluenesulfonic acid to afford a-[(3-morpholinoestra- 1,3,5( l0),8(9), l 4-pentaen-l 7a-yliden)aminoxy ]propionic acid.

Hydrolysis of the latter novel tetracyclic intermediates yields thecorresponding l7-keto compounds of the following structural formula a-l3-Morpholinoestral ,3 ,5( l 0),8(9), l 4-pentaenl 701-yliden)aminoxy]propionic acid is thus heated with dilute hydrochloricacid to produce 3-morpholinoestral ,3,5(10),8(9 ),l4-pentaen-I7-one.Conversion of the instant tetracyclic pentaene novel intermediates topharmacologically useful substances is effected by processes described,for example, in U.S. Pat. No. 3,325,481, issued June 13, 1967. By thoseprocesses of selective hydrogenation of the 14(15) double bond, chemicalreduction of the 8(9) double bond, Birch reduction of the A-ring andacid hydrolysis, there are produced the diketones of the followingstructural formula wherein R is as hereinbefore defined. As is describedin the latter patent, those diketones are useful as intermediates in themanufacture of pharrnacologically active compounds. Estr-4-ene-3,17-dione thus can be converted, by the processes describedtherein, to l7a-ethynylestr-4-ene-3/3,l7B-diol 3,17- diacetate, asubstance known for its potent progestational properties.

The invention will appear more fully from the examples which follow. Theexamples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited therebyeither in spirit or in scope as many modifications both in materials andmethods will be apparent from this disclosure to those skilled in theart. ln these examples temperatures are given in degrees Centigrade C.).Quantities of materials are expressed in parts by weight unlessotherwise noted.

EXAMPLE 1 thus obtained (+)aminoxypropionic acid, melting at aboutl32-l34 and exhibiting an optical rotation, in water, of +l44. Furtherpurification is effected by trituration with ethanol followed byrecrystallization from aqueous ethanol, thus affording small needlelikecrystals, melting at about l38-138.5 and displaying an optical rotation,in water, of +140.

EXAMPLE 2 To a solution of 16.77 parts of 2-methyl-2-[2-(6- morpholino-l,2,3,4-tetrahydronaphthl yliden)ethyllcyclopentane-l ,3-dione in 54parts of tetrahydrofuran is added 1 part of (+)aminoxypropionic acidfollowed by 2 parts of water. The resulting reaction mixture is kept at30 and stirred for approximately hours, then is stripped of solvent bydistillation under reduced pressure. The residual oily material isdissolved in lzl ether-benzene and that organic solution is washedsuccessively with water, dilute aqueous sodium hydroxide and water untilneutral. The combined alkaline and aqueous washings are neutralized withacetic acid and the acidic mixture is extracted with benzene. Thebenzene solution is washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure to afford afoamlike residue consisting of a-{ 2-methyl-2-[2-(6-morpholino-l,2,3,4-tetrahydronaphthl yliden )ethyl1-3-oxocyclopentl-ylidenaminoxy}propionic acid, which compound displays an opticalrotation, in chloroform, of -3S.

EXAMPLE 3 A mixture containing 2 parts of a-{2-methyl-2-[2-(6-morpholinol ,2,3 ,4-tetrah ydronaphthl -yliden )ethyl-3-oxocyclopent-l-ylidenaminoxy} propionic acid, 53 parts of benzene and0.2 part of p-toluenesulfonic acid monohydrate is heated at the refluxtemperature under nitrogen for about 1% hours, then is cooled to roomtemperature, washed with water, dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. The residual crudeproduct, isolated as a tan foam, exhibits an optical rotation, inchloroform, of +285 and also ultraviolet absorption maxima at about 229and 324 millimicrons. That material is twice recrystallized from etherto afford rosette-like crystals of pure tit-[(3- morpholinoestral,3,5(10),8(9),14-pentaen-17ayliden)aminoxy]propionic acid, melting atabout 181l831 with decomposition and exhibiting an optical rotation, in

chloroform, of +100.

EXAMPLE 4 To a solution of 3.18 parts of dl 3-morpholinoestra-1,3,5(10),8(9),14-pentaen-17-one in 45 parts of tetrahydrofuran is added1.1 parts of (+)aminoxypropionic acid followed by 2 parts of water. Theresulting reaction mixture is stirred, under nitrogen, at roomtemperature for about 72 hours, then is evaporated to dryness underreduced pressure. The resulting residue is dissolved in benzene and thebenzene solution washed with water, then extracted with dilute aqueoussodium hydroxide. The semisolid which forms during the extraction iscombined with the extracts and that mixture is neutralized with aceticacid. Extraction of the acidic mixture with benzene affords an organicsolution, which is washed with water, then dried over anhydrous sodiumsulfate and evaporated to dryness to afford a darlt foamlike residue.That material is purified by clarification with decolorizing carbon inether, thus affording a 50:50 mixture of the diastereomeric tit-[(3-morpholinoestra-l ,3,5(10),8(9),14-pentaen-17ayliden)aminoxy]propionicacids, characterized by an optical rotation in chloroform, of +1 8. 11displays ultraviolet absorption maxima at about 234.5 and 325millimicrons. Fractional crystallization of that material from etherresults in a single pure isomer, melting at about l86-188 withdecomposition and exhibiting an optical rotation, in chloroform, of-52.5.

EXAMPLE 5 To a solution of 14 parts of 2-methyl-2-[2-(6-morpho1inol,2,3,4-tetrahydronaphth-l-yliden )ethyllcyclopentane- 1 ,3- dione in 45parts of tetrahydrofuran is added 2 parts of water and the resultingmixture is cooled to -20. At that point 1.47 parts of(+)oz-aminoxyisocaproi'c acid is added and the mixture is stirred atthat temperature for about 120 hours. At the end of that time thesolvent is removed by distillation under reduced pressure and theresidue is extracted with benzene. The benzene solution is extractedseveral times with dilute aqueous sodium hydroxide and those combinedextracts are acidified with acetic acid. Extraction of the resultingacidic mixture with benzene-ether affords a solution, which is washedwith water, dried over anhydrous sodium sulfate and stripped of solventto afford a-{2-methyl-2-[2-(6'morpholinol,2,3,4-tetrahydronaphth-1-yliden)ethyl]-3-oxocyclopent-1- ylidenaminoxyisocaproic acid, which is characterized by an optical rotation, inchloroform, of 38.5.

EXAMPLE 6 A mixture containing 105.6 parts of benzene and 0.272 part ofp-toluenesulfonic acid monohydrate is partially distilled to achievedryness, at which time 3 parts of a-{2-methyl-2-[2-(6-morpholino-1,2,3,4-tetrahydronaphth-1-y1iden)ethy1]-3-oxocyclopent-l-ylidenzminoxyisocaproic acid is added. The resulting reaction mixture is distilledslowly over a period of about 90 minutes in a nitrogen atmosphere, atthe end of which time it is cooled, washed with water, dried overanhydrous sodium sulfate and concentrated to dryness by distillationunder reduced pressure. The resulting residue is extracted into etherand the organic solution is decolorized with activated carbon, then isstripplid of solvent under reduced pressure to afford 2.32 parts ofoz-[(3-morpholinoestra- 1,3 ,5( 1 ),8(9), 1 4-pentaen-l 7a-yliden)aminoxyllisocaproic acid, characterized by an optical rotation, inchloroform, of

EXAMPLE 7 A mixture containing 1 part of a-[(3-morpholinoestra- 1,3 ,5(l 0),8(9), 1 4-pentaen- 1 701yliden )aminoxy lisocaproic acid, 0.2 partof diazomethane and 20 parts of methanol is allowed to stand at roomtemperature for about 5 minutes. At the end of that time the solvent isremoved by distillation under reduced pressure. The resulting residue isextracted into ether-benzene and the organic solution is washedsuccessively with dilute aqueous potassium bicarbonate and water, thendried over anhydrous sodium sulfate and stripped of solvent underreduced pressure. Crystallization of the residual material from etheraffords 0.265 part of methyl (X-[(3-morpholinoestra-l,3,5(10),8(9),l4-pen.taen-17aylidenaminoxylisocaproate,melting at about l54.5l56.5 and exhibiting an optical rotation, inchloroform, of +805". From the mother liquors there is obtained anadditional 0.285 part of that same material.

EXAMPLE 8 To a solution of 1.4 parts of 2-meth yl-2-[2-( o-morpholino-1,2,3 ,4-tetrahydronaphthl -y1iden )ethyl lcyclopentane-l ,3 dione in4.5 parts of tetrahydrofuran is added successively 0.2 part of water and0.15 part of a-hy|drazinoisocaproic acid. The mixture becomeshomogeneous after stirring for about 24 hours, at the end of which timeit is stored at room temperature for an additional 24 hours. Thereaction mixture is then diluted with ether and benzene and extractedwith dilute aqueous sodium hydroxide. These alkaline extracts arecombined, washed with ether, then acidified to pH 4 with acetic acid.That acidic mixture is extracted with ether and the ether layer isseparated, washed with water, then concentrated to dryness under reducedpressure to afford a-{2-methyl-2-[2-(6- morpholino-l,2,3,4-tetrahydronaphth- 1 -yliden)ethyl1-3-oxocyclopent-l-ylidenhydrazino}isocaproic acid, characterizedby an optical rotation, in chloroform, of 1 2.

EXAMPLE 9 When an equivalent quantity of a-{2-methyl-2-[2-(6-morpholino-l,2,3,4-tetrahydronaphth-1-yliden)ethyl]-3-oxocyclopent-1ylidenhydrazino}isocaproicacid is substituted in the procedure of example 3, there is produceda-[(3- morpholinoestra-l ,3,5(10),8(9),14-pentaenl 7ayliden)hydrazinolisocaproic acid.

EXAMPLE 10 To a solution of 12 parts of 2methyl-2-{2-(6-methoxyl,2,3,4-tetrahydronaphthl -yliden)ethyl1cyclopentane-1 ,3- dione in 113parts of tetrahydrofuran is added 4.2 parts of water and the resultingmixture is cooled to approximately -20, at which time 2.1 parts ofaaminoxypropionic acid is added. The resulting reaction mixture isstirred at approximately 20 for about hours, at the end of which timethe solvent is removed by distillation under reduced pressure and theresulting residue is diluted with benzene, then washed with water.Extraction of that organic solution with dilute aqueous sodium hydroxidefollowed by acidification with acetic acid of those extracts andextraction of the acidified solution with benzene affords an organicsolution, which is washed with water, dried over anhydrous sodiumsulfate and stripped of solvent under reduced pressure, thus affordinga-{ 2-methyl-2- [2-(6-methoxy-l,2,3,4-tetrahydronaphth-1-yliden)ethyl]-3-oxocyclopent-l-ylidenaminoxy}propio'nic acid, characterized by anoptical rotation in chloroform, of'40.

EXAMPLE 11 A mixture of 176 parts of benzene and 0.1 part ofptoluenesulfonic acid monohydrate is slowly distilled until anhydrous.To that solution is then added 4 parts of a-{Z-methyl- 2-[2-(6-methoxy-l,2,3,4-tetrahydronaphth-1-yliden)ethyl]-3- oxocyclopent-l-ylidenaminoxy}propionic acid and the resulting mixture is slowly distilled over aperiod of about minutes. The mixture is then cooled at 05, washed withwater, dried over anhydrous sodium sulfate and stripped of solvent bydistillation under reduced pressure. The resulting residue is extractedinto ether and the organic solution is decolorized with activatedcarbon, then stripped of solvent to afford the crude product.Purification of that material by recrystallization form ether yieldsa-[(3-methoxyestral,3,5( l 0),8(9), l 4'pentaenl7a-yliden)aminoxyllpropionic acid, melting at about l47l53.5 anddisplaying an optical rotation, in chloroform, of +1 l2.5.

EXAMPLE 12 When an dimethylamino-1,2,3 ,4-tetrahydronaphthlyliden)ethyl]cyclopentane-l ,3-dione is substituted in the procedure ofexample 2, there is obtained a-{2-methyl-2-[2-( 6-dimethylamino-1 ,2,3,4-tetrahydronaphthl -yliden)ethyl ]-3- oxocyclopentl -ylidenaminoxy}propionic acid.

EXAMPLE l3 The substitution of an equivalent quantity of a{2-methyl-2-[2-( 6-dimethylamino-l ,2 ,3 ,4-tetrahydronaphthl yliden )ethyl 1-3-oxocyclopentl -ylidenaminoxy propionic acid in the procedure of example3 results in a-[(3- dimethylaminoestra-l ,3 ,5( l 0),8(9), l 4-pentaen-1 7ayliden)aminoxy]propionic acid.

EXAMPLE l4 By substituting an equivalent quantity of 2-methyl-2-[2-(6-ethoxyl ,2,3 ,4-tetrahydronapth-1-yliden)ethyllcyclopentane- 1,3-dioneand otherwise proceeding according to the processes described in example2, there is produced a{2- methyl-2-]2-( 6-ethoxyl ,2 ,3,4-tetrahydronapthlyliden)ethyl]-3-oxocyclopent-l-ylidenaminoxy}propionic acid.

EXAMPLE The substitution of an equivalent quantity of a{2-methyl-2- [2-(6-ethoxy-l ,2,3 ,4-tetrahydronaphthl -yliden )ethyl -3-oxocyclopent-l-y}isocaproic acid in the procedure of example 3 results in[(-ethoxyestra-1,3,5(10,8(9),l4-pentaen-l7acid.

EXAMPLE 16 A mixture containing 2 parts of ai2-methyl-2-[2-(6-morpholinol ,2,3 ,4-tetrahydronaphthl-yliden)ethyl]-3-oxocyclopent-l-ylidenaminoxy isocaproic acid, 0.5 partof diazomethane, l0 parts of ether and 20 parts of methanol is allowedto stand at room temperature for about 5 minutes. Removal of the solventand excess reagent by distillation under reduced pressure affords methyla-{ 2-methyl-2-[2-(6 morpholino-l ,2,3 ,4-tetrahydronaphthl-yliden)ethyl]-3-oxocyclopentl -ylidenaminoxy }isocaproate.

To a solution of the latter methyl ester in 35 parts of benzene is added0.09 part of p-toluenesulfonic acid and the resulting reaction mixtureis slowly distilled, under nitrogen, for about 3 hours. At the end ofthat time the mixture is cooled and 0.09 part of potassium carbonate isadded. That solution is then washed successively with dilute aqueouspotassium bicarbonate and water, dried over anhydrous sodium sulfate andstripped of solvent under reduced pressure. The resulting residue isdissolved in ether and that solution is clarified by means ofdecolorizing carbon. Distillation of the solvent under reduced pressureaffords methyl a-[(3-morpholinoestra- 1,3,5( l0),bh8(9),l4-pentaen-l7a-yliden) aminoxy] isocaproate, characterized by an optical rotation,in chloroform, of +80.5. It is identical with the product of example 7.

What is claimed is:

1. In a process for the selective manufacture of steroidal derivativespossessing either the d or I stereochemical configuequivalent quantityof 2-methyl-2-[2-(6- ration, the step which comprises reacting a steroidintermediate of the following formula wherein R is lower alkyl and Y isaminoxy or hydrazino, to afford a compound of the following formulawherein R, R and X are as hereinbefore defined and Z is oxa or imino.

2. The process of claim 1, wherein Y is aminoxy and Z is oxa.

3. The process of claim 1, wherein Y is hydrazino and Z is imino.

4. As in claim 1, the process which comprises reacting 2- methyl-2-[2-(o-morpholino-l ,2,3,4-tetrahydronaphthlyliden)ethyl]cyclopentane-l,3-dione with optically active 11-aminoxypropionic acid to afford unequal amounts of the diastereomeric a{2-methyl-2[2-(6-morpholino-1 ,2,3,4-tetrahydronaphth-1-yliden)ethyl]3-oxocyclopent-lylidenaminoxy} propionicacids.

5. As in claim 1, the process which comprises reacting 2- methyl2-[2-(6-morpholinol ,2,3,4-tetrahydronaphth- 1yliden)ethyllcyclopentane-l,3-dione with optically active 0:-aminoxyisocaproic acid to afford unequal amounts of the diastereomerica- 2-methyl-2-[2-( 6-morpholino 1,2,3 ,4tetrahydronaphthl-yliden)ethyl]-3-oxocylopentl ylidenaminoxy }isocaproic acids.

6. As in claim 1, the process which comprises reacting 2- methyl-2-[2-(6-methoxyl ,2,3,4-tetrahydronaphthlyliden)ethyllcyclopetane-l,3-dione with optically active (1-aminoxypropionic acid to afford unequal amounts of the diastereomeric a-2-methyl-2-[2-( o-methoxy-l ,2,3,4- tetrahydronaphthl -yliden )ethyl]-3-oxocyclopent-lylidenaminoxy propionic acid.

7. A compound ofthe formula N-Z-OHO O OH wherein X is lower alkoxy,di-(lower ahkyl)amino, pyrrolidino, piperidino, morpholino, pipecolino,piperazino or hexamethylenimino, Z is oxa or imino and R and R are loweralkyl.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 5, 625,9 Dat d December 7, 97

Inventor) Raphael Pappo and Robert T. Nicholson identified patent shownbelow:

Column 9, formula,

NHHCHCOOH II I R, n 1 C3 should be a NNHCHCOOH Column 10, line 5, ")etn1]5-" should be )ethyl1-3- l Column 10, line 8, moropholino" should be-morpnolino- Column 10, line 12, "-ylidenaminoxy propionic'f shou be-ylidenaminoxy}propionic Signed and sealed this 27th. day of June 1972..

(SEAL) Attest:

EDWARD M.FLETCHER, JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

2. The process of claim 1, wherein Y is aminoxy and Z is oxa.
 3. Theprocess of claim 1, wherein Y is hydrazino and Z is imino.
 4. As inclaim 1, the process which comprises reacting2-methyl-2-(2-(6-morpholino-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)cyclopentane-1,3-dione with optically active Alpha-aminoxypropionic acid to afford unequal amounts of the diastereomericAlpha -2-methyl-2(2-(6-morpholino-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)3-oxocyclopent-1-ylidenaminoxy propionic acids.
 5. As in claim 1, theprocess which comprises reacting 2-methyl2-(2-(6-morpholino-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)cyclopentane-1,3-dione with optically active Alpha -aminoxyisocaproic acid to affordunequal amounts of the diastereomeric Alpha -2-methyl-2-(2-(6-morpholino-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)-3-oxocyclopent-1-ylidenaminoxy isocaproic acids.
 6. As in claim 1, theprocess which comprises reacting2-methyl-2-(2-(6-methoxy-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)cyclopetane-1,3-dionewith optically active Alpha -aminoxypropionic acid to afford unequalamounts of the diastereomeric Alpha -2-methyl-2-(2-(6-methoxy-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)-3-oxocyclopent-1-ylidenaminoxy propionic acid.
 7. A compound of theformula
 8. As in claim 7, a compound of the formula
 9. As in claim 7,the compound which is Alpha -2-methyl-2-(2-(6-morpholino-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)3-oxocyclopent-1-ylidenaminoxy propionic acid.
 10. As in claim 7, thecompound which is Alpha -2-methyl-2-(2-(6-moropholino-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)-3-oxocyclopent-1-ylidenaminoxy isocaproic acid.
 11. As in claim 7, thecompound which is Alpha -2-methyl-2-(2-(6-methoxy-1,2,3,4-tetrahydronaphth-1-yliden)ethyl)-3-oxocyclopent-1-ylidenaminoxy propionic acid.